DESCRIPTION: Toxoplasmic encephalitis (TE) is a life threatening condition in patients with defects in T cell function. The aim of these studies is to understand the mechanisms that maintain T cell responses required for resistance to T. gondii and how T cells mediate control of parasite replication in the brain. The progressive loss of T cells during AIDS predisposes these patients to TE, and it has been proposed that the dysregulated activation of the NF-kB family of transcription factors seen in these patients results in increased susceptibility of T cells to apoptosis and contributes to the loss of T cells. Similarly, NF-kB2-/- mice infected with T. gondii develop protective T cell responses, but gradually lose their T cells and succumb to TE. The mechanism that leads to the loss of T cells is unclear but is associated with reduced levels of proliferation, high levels of apoptosis, and increased expression of IL-2 and Fas in chronically infected mice. In order to understand the role of NF-KB in the maintenance of T cell responses required for resistance to TE, experiments will assess whether NF-kB2 has a direct or indirect role in preventing apoptosis and if the loss of T cells observed in chronically infected NF-kB2 -/- mice can be reversed. Although these studies will provide new information on how T cell response required for resistance to TE are maintained they do not provide information on the effector responses mediated by T cells in the brains. Therefore, studies will be performed to assess the role of the CD40/CD40L interaction in resistance to TE. The interaction of CD40 (expressed on hematopoietic and non-hematopoietic cells) and CD40L (expressed on activated T cells) is required for resistance to TE in mice, and patients with defects in this interaction are also susceptible to TE. Our studies indicate that CD40L is not required for the generation of protective IFN-gamma responses in vivo, instead, CD40L may activate infected cells to control parasite replication or may be required for the generation of parasite specific cytotoxic T lymphocytes (CTL). In vitro experiments will be performed to understand the mechanism that allows CD40L to activate macrophages to inhibit parasite replication and to determine if CD40L can activate non-hematopoeitic cells to control parasite replication. In vivo studies will assess the role of CD40L in the generation of CTL responses and if administration of soluble (s) CD40L can be used to treat TE. Together, these studies will provide new information on the factors associated with the maintenance of T cell responses required for resistance to TE land, the T cell effector functions required for control of parasite replication in the brain.